Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease
| Autor: | Netanja I. Harlianto, Marcel A.G. van der Heyden, Aart-Jan van Weert, Meye Bloothooft, Sophie M de Wilde, Emma J van Hattum, Laura van der Schoor |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
heart failure 030204 cardiovascular system & hematology Pharmacology Cystic fibrosis Catalysis IK1 lcsh:Chemistry Inorganic Chemistry 03 medical and health sciences 0302 clinical medicine inward rectifier channel medicine Physical and Theoretical Chemistry agonist lcsh:QH301-705.5 Molecular Biology Spectroscopy Membrane potential Kir2 Chemistry Mechanism (biology) Inward-rectifier potassium ion channel Andersen syndrome Organic Chemistry Skeletal muscle General Medicine Potentiator medicine.disease Potassium channel Computer Science Applications 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) lcsh:QD1-999 Drug development |
| Zdroj: | International Journal of Molecular Sciences, Vol 21, Iss 5746, p 5746 (2020) |
| ISSN: | 1422-0067 |
| Popis: | Inward rectifier potassium ion channels (IK1-channels) of the Kir2.x family are responsible for maintaining a stable negative resting membrane potential in excitable cells, but also play a role in processes of non-excitable tissues, such as bone development. IK1-channel loss-of-function, either congenital or acquired, has been associated with cardiac disease. Currently, basic research and specific treatment are hindered by the absence of specific and efficient Kir2.x channel activators. However, twelve different compounds, including approved drugs, show off-target IK1 activation. Therefore, these compounds contain valuable information towards the development of agonists of Kir channels, AgoKirs. We reviewed the mechanism of IK1 channel activation of these compounds, which can be classified as direct or indirect activators. Subsequently, we examined the most viable starting points for rationalized drug development and possible safety concerns with emphasis on cardiac and skeletal muscle adverse effects of AgoKirs. Finally, the potential value of AgoKirs is discussed in view of the current clinical applications of potentiators and activators in cystic fibrosis therapy. |
| Databáze: | OpenAIRE |
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